Regulation of GABAergic Inhibition by Serotonin …zhenyan/5HT+GABA-review.pdfthe frontal lobes. The anatomical organization of primate PFC can be divided into three major subregions:

Introduction

The serotonergic system plays a key role inregulating emotional processes and cognitive

behaviors in the central nervous system (CNS)(1–3). Dysfunction of serotonergic neuro-transmission has long been implicated inthepathogenesis of neuropsychiatric disordersincluding schizophrenia, depression, and anxi-ety (4–8). The new generation of antipsychoticagents, which constitutes a major advance inthe treatment of schizophrenia, has high affin-

Molecular Neurobiology 1 Volume 26, 2002

Molecular NeurobiologyCopyright © 2002 Humana Press Inc.All rights of any nature whatsoever reserved.ISSN0893-7648/02/26(2-3): 000–000/$0.00

Regulation of GABAergic Inhibition by Serotonin Signalingin Prefrontal Cortex

Molecular Mechanisms and Functional Implications

Zhen Yan*

Department of Physiology and Biophysics, SUNY at Buffalo, 124 Sherman Hall, Buffalo, NY 14214

Abstract

Serotonergic neurotransmission in prefrontal cortex (PFC) plays a key role in regulating emo-tion and cognition under normal and pathological conditios. Increasing evidence suggests thatserotonin receptors are involved in the complex regulation of GABAergic inhibitory transmissionin PFC. Activation of postsynaptic 5-HT2 receptors in PFC pyramidal neurons inhibits GABAA-receptor currents via phosphorylation of GABAA receptor γ2 subunits by RACK1-anchored PKC.In contrast, activation of postsynaptic 5-HT4 receptors produces an activity-dependent bi-direc-tional regulation of GABA-evoked currents in PFC pyramidal neurons, which is mediated throughphosphorylation of GABAA-receptor β subunits by anchored PKA. On the presynaptic side,GABAergic inhibition is regulated by 5-HT through the activation of 5-HT2, 5-HT1, and 5-HT3

receptors on GABAergic intereneurons. These data provide a molecular and cellular mechanismfor serotonin to dynamically regulate synaptic transmission and neuronal excitability in the PFCnetwork, which may underlie the actions of many antidepressant and antipsychotic drugs.

Index Entries: Serotonin receptors; prefrontal cortex; GABAA receptors; inhibitory synaptictransmission; PKC; RACK1; PKA; AKAP; modulation.

* Author to whom are correspondence and reprintrequests should be addressed. E-mail: [email protected]

ity for serotonin receptors (9–12). Drugs effec-tive in treating depression also act mainly onthe serotonergic system (13,14).

The serotonergic system has a broadanatomical distribution in the CNS, mediatingwidespread effects in central neurons. One ofthe main target structures for the serotonergicsystem is prefrontal cortex (PFC), a collectionof cortical areas in the most anterior portion ofthe frontal lobes. The anatomical organizationof primate PFC can be divided into three majorsubregions: 1) dorsolateral, 2) orbitofrontal,and 3) medial PFC. In rats the prelimbic, infral-imbic, and ventral anterior cingulate cortexrepresent the major subdivisions of PFC (15).Based on their patterns of neural connectivity,these regions are thought to be related func-tionally to PFC in the primate (16–18). Theentire PFC is highly innervated by serotonergicprojections from the brain stem raphe nucleiand dopaminergic projections from the ventraltegmental area (19,20). The processed and inte-grated information is transmitted from PFC todistributed neural networks including cortex,thalamus, hypothalamus, brain stem, basalganglia, and limbic areas. All subregions ofPFC are robustly interconnected, suggestingthat they participate in concert in central exec-utive functions. The PFC has long been associ-ated with high-level, “executive” processesneeded for complicated goal-directed behavior(21). Functional studies in primates emphasizethat PFC is particularly critical for a form ofshort-term information storage described as“working memory” (22). The firing of somePFC neurons increases throughout the delayperiod of a delayed-response task when infor-mation must be “held” momentarily and usedsubsequently to guide correct responses (22).The excitability and tuning of PFC neurons aresubject to modulatory influences by serotoninand many other neurotransmitters (23). Thedamage of PFC in humans results in distur-bances in a variety of functions, such as atten-tion, memory, response selection, andplanning.

PFC is composed of two major neuronal pop-ulations: 1) glutamatergic pyramidal principal

neurons and 2) GABAergic interneurons. LocalGABAergic neurons form numerous synapseson pyramidal projection neurons (24), exertingstrong inhibitory control on the excitatory out-put of PFC. One important function of theGABAergic inhibition in PFC is to control thetiming of neuronal activity during cognitiveoperations and thereby shape the temporal flowof information (25). Serotonergic projections tar-get both types of PFC neurons in a synaptic andnonsynaptic manner (26). Recent evidenceshows that serotonin (5-HT) neurotransmissionis predominantly paracrine, raising the possibil-ity that 5-HT can act on receptors that are dis-tant from its release site (27). Specific changes ofthe PFC serotonin system and PFC neuronalactivity have been found in patients with neu-ropsychiatric disorders (4,5,7,28–31). It suggeststhat in PFC, serotonin plays a crucial andunique role in neural computation associatedwith the execution of complex tasks involved incognition and emotion.

The pleiotropic functions of serotonin areafforded by the concerted actions of multipleserotonin receptor subtypes. The 5-HT recep-tors are composed of several families that canbe grouped on the basis of conserved struc-tures and signaling mechanisms (32). The 5-HT1 class of receptor (5-HT1A, 1B, 1D, 1E, 1F)couples to Gi/o proteins to inhibit adenylatecyclase. The 5-HT2 class of receptor (5-HT2A,2B,2C) couples to Gq proteins to stimulatethe turnover of phospholipids. The 5-HT4 classof receptor (5-HT4, 6, 7) couples to Gs proteins tostimulate adenylate cyclase. The 5-HT5 class ofreceptor (5-HT5A, 5E) has unknown coupling. Inaddition, the 5-HT3 receptor is a ligand-gatedchannel. Serotonin can have both inhibitoryand excitatory functions in neuronal networksthrough the coupling of different 5-HT recep-tors to distinct ion channels (33). Such a mech-anism allows serotonin to simultaneouslyremodel excitability in a functionally appropri-ate manner in a wide variety of cell types andneuronal circuits.

Mice lacking different serotonin receptorsexhibit diverse phenotypes including epilepsysyndrome (34), increased impulsive aggression

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Molecular Neurobiology Volume 26, 2002

(35), elevated anxiety, and antidepressant-likeresponse (36). Given the critical involvement ofGABAA receptor-mediated inhibitory synaptictransmission in epilepsy, anxiety, and depres-sion (37) the phenotypes in 5-HT receptorknockout mice may be correlated to changes inGABAergic transmission of PFC neurons.Indeed, selective alterations in GABAA recep-tors, GABA content and GABAergic interneu-rons have been discovered in PFC of patientswith mental disorders (30,38–40). These linesof evidence suggest that GABAA receptor isone of the cellular substrates of serotonin inPFC, and dysregulation of GABAergicinhibitory transmission by serotonin in PFC isa major contributing factor in neuropsychiatricdiseases (41).

The GABAA receptor contains an intrinsicchloride channel which is thought to be a het-eropentameric structure, assembled by com-bining homologous subunits from fivedifferent classes: α (1–6), β (1–4), γ (1–3), δ andε (1–2) (37). The subunit composition ofGABAA receptors critically affects the func-tional properties of GABAA channels. MultiplePKA and PKC phosphorylation sites have beenidentified in several GABAA-receptor subunits(42). Protein phosphorylation exerts a power-ful regulation of GABA-activated currents inrecombinant and native GABAA channels(43–46). Reviewed here are some data showinghow serotonin, by activating different recep-tor-mediated signaling cascades, regulateGABAA-receptor channels and GABAergicinhibitory synaptic transmission in PFC neu-rons.

Regulation of GABAA-ReceptorChannels and GABAergic SynapticTransmission by 5-HT2 Signaling

Multiple G-protein-coupled 5-HT receptorshave been identified in PFC pyramidal neu-rons (47), among which 5-HT2A is one of themost prominent subtypes expressed in almostall (approx 90%) of these cells (48). Application

of 5-HT2-class agonists produces a reduction ofGABAA currents in most of PFC pyramidalneurons, and this effect is blocked by 5-HT2

antagonists, confirming the mediation by 5-HT2 receptors (48). Postsynaptic 5-HT2A recep-tors are concentrated in apical dendritesproximal to the soma in PFC pyramidal neu-rons (49), while GABAA receptors exhibit acompartmentalized distribution on postsynap-tic domains of GABAergic synapses on thesoma and proximal dendrites (50). The overlapin the expression pattern between 5-HT2A andGABAA receptors suggests that they may beco-localized at some synapses in PFC pyrami-dal neurons. Such spatial organization wouldenable direct serotonergic modulation of localresponses to inhibitory input, which offers adynamic regulatory mechanism of synapticintegration, hence neuronal output.

Several lines of electrophysiological evi-dence indicate that the 5-HT2 modulation ofGABAA-receptor currents is through a mecha-nism involving stimulation of phospholipidhydrolysis and activation of PKC (48). More-over, in vitro kinase assays show that treat-ment of PFC slices with a 5-HT2 receptoragonist significantly increases the kinase activ-ity of PKC towards GABAA-receptor γ2 sub-unit, but not the β2 subunit over its alreadyhigh basal level of phosphorylation (48). Theseresults suggest that activation of 5-HT2 recep-tors in PFC can enhance the PKC catalyticactivity, and potentiate PKC phosphorylationof GABAA receptors in a subunit-specific man-ner. Consistent with previous studies on PKCregulation of recombinant GABAA receptors(45,51), the data have revealed that increasedPKC phosphorylation of Ser-327 in γ2 subunitby 5-HT2 signaling may play a major role inmediating the serotonergic modulation ofGABAA currents in PFC neurons (48).

The broad substrate selectivity of PKCmakes it essential to control the specificity ofthis enzyme. Emerging evidence has suggestedthat one important mechanism for signalingenzymes to achieve fidelity and efficacy of sig-nal transduction is through association withanchoring proteins that target to specific sub-

Serotonin Signaling in Prefrontal Cortex 3


cellular localization (52–54). The compartmen-talization and functions of PKC isoforms arealso critically dependent on anchoring proteins(55–57). RACK1, one member of the RACKfamily proteins, binds only activated PKC iso-forms in a selective manner (58). It facilitatesthe membrane translocation of PKC and PKCphosphorylation of specific substrates (59–61).RACK1 is found to strongly associate withneuronal GABAA receptors in in vitro assays(62), suggesting that RACK1 may be responsi-ble for targeting PKC to GABAA-receptorchannels and allowing PKC to effectivelyphosphorylate these receptors. Consistent withthis, when the PKC-RACK1 complex is dis-rupted by a PKC-anchoring inhibitory peptidederived from RACK1, which may lead to theremoval of PKC from the proximity of GABAA

receptors, the ability of 5-HT2 agonists toinhibit GABAA currents is eliminated (48). Incontrast, disrupting the binding of PKC toanother anchoring protein AKAP79 (63) doesnot affect the 5-HT2 regulation of GABAA cur-rents. These results suggest that targeting ofactivated PKC to GABAA receptors via RACK1plays a critical role in the regulation of GABAA

currents by the 5HT2/PKC signaling pathway.Thus, activation of 5-HT2 receptors causes areduction of GABAA-receptor currents throughRACK1-anchored PKC (see Fig. 1), which sug-gests that serotonin signaling may suppressGABAergic inhibition in PFC circuits.

Recordings in frontal cortical slices haveshown that an application of 5-HT throughactivation of 5-HT2A receptors induces a large,desensitizing enhancement of spontaneousinhibitory postsynaptic currents (sIPSCs), butdecreases evoked eIPSCs in pyramidal neu-rons (64). The increase in both frequency andamplitude of sIPSCs and its TTX sensitivitysuggest that 5-HT2A receptors can enhanceGABAergic inhibitory inputs to PFC pyrami-dal neurons. One potential reason is that theactivation of 5-HT2A receptors on corticalGABAergic interneurons leads to an increasein their excitability (64), possibly by inhibitingan inward rectifying potassium conductance(65,66) or by activating a cation nonselectivecurrent (67,68) resulting in the enhancedGABA transmission. On the other hand, the 5-HT reduction of eIPSC amplitude, but not thepaired-pulse depression (64), suggests that 5-

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Fig. 1. A diagram illustrating the signal transduction cascade underlying 5-HT2 regulation of GABAA-receptorchannels in PFC pyramidal neurons. Activation of 5-HT2 receptors stimulates phospholipase C β isoform (PLCβ),leading to the release of ionsitol-1,4,5-triphosphate (IP3) and diacylglycerol (DAG) through the hydrolysis ofmembrane phosphoinositol lipids. Activated PKC is targeted to GABAA receptors by the association with itsanchoring protein RACK1, leading to the phosphorylation of GABAAR subunits and reduction of GABAAR-medi-ated currents.

HT can also decrease the postsynapticresponse to GABA in pyramidal neurons, pos-sibly through a 5-HT2-mediated intracellularsignaling cascade (48). This 5-HT2-inducedsuppression of postsynaptic GABAA-receptorsmay provide a negative feedback mechanismfor 5-HT2 regulation of GABAergic inhibitionin PFC circuits.

Regulation of GABAA-ReceptorChannels by 5-HT4 Signaling

In addition to 5-HT2A receptors, anotherserotonin receptor subtype that is enriched inPFC pyramidal neurons is 5-HT4 (69). About60% of these cells express 5-HT4 receptors (48).Emerging evidence contends for a significantrole of 5-HT4 receptors in anxiolysis and cog-nition (70). For example, the anxiolytic effectof diazepam (an enhancer of GABA response)is inhibited by application of 5-HT4-receptorantagonists, particularly when the serotoner-gic tone is high (71). Activation of 5-HT4

receptors exerts ameliorative effects on spatialmemory tests and reverses cognitive-perfor-mance deficits induced by cholinergic hypo-function (70). In addition, marked reduction in5-HT4-receptor expression has been found inhippocampus and frontal cortex of patientswith Alzheimer’s disease (72), consistent withthe potential role of 5-HT4 receptors in cogni-tion. These findings suggest that 5-HT4 recep-tors may play an important role in regulatingion channel activity, therefore affecting synap-tic plasticity and neuronal excitability, whichis fundamental in learning and memory. Pre-vious studies have found that 5-HT4-receptoractivation exerts an excitatory impact on neu-rons through regulating different voltage-dependent ion channels (73–76). A recentstudy (77) has identified the GABAA-receptorchannel as a molecular target of 5-HT4 recep-tors in PFC.

Application of 5-HT4-receptor agonistscauses a bi-directional modulation of GABAA

currents in PFC pyramidal neurons, with

enhancement in some cells and reduction inothers. The dual effects are mediated by PKA,because application of PKA activators mimicksthe dual effects of 5-HT4 agonists on GABAA

currents, while PKA inhibitors block the bi-directional regulation of GABAA currents by 5-HT4 agonists (77). Due to the broad substrateselectivity of PKA, subcellular targetingthrough association with anchoring proteins(AKAPs) has been effected as an importantmechanism by which PKA achieves specificityin signal transduction (78–80). Dialysis of theneurons with a peptide that can specificallydisrupt the interaction between AKAPs andPKA (78) significantly attenuates the dualeffects of 5-HT4 agonist on GABAA currents(77), suggesting that the 5-HT4 modulation ofGABAA-receptor channels is a highly localizedevent that requires the fraction of PKAanchored on AKAPs.

Both PKA-induced enhancement andreduction of GABAA currents have beenreported in recombinant systems and nativeneurons (43,81). The dual effects of PKA seemto be attributable to phosphorylation of dif-ferent GABAA-receptor β subunits, sinceenhancement occurs when β3 subunit-con-taining receptors are phosphorylated by PKAon both S408 and S409, whereas reductionoccurs when β1 subunit-containing receptorsare solely phosphorylated on S409 (82). How-ever, single cell RT-PCR profiling results showthat both β1 and β3 subunits are co-expressedin PFC pyramidal neurons (77), suggestingthat reasons other than the differential expres-sion of β subunits may underlie the dualeffects of 5-HT4 agonists on GABAA currents.A set of experiments suggests that the bi-directional modulation of 5-HT2 receptors onGABAA currents is dependent on the basalphosphorylation states of GABAA receptors(77). In the same neuron, manipulations thatdecrease PKA activation levels switch theeffect of 5-HT4 receptors on GABAA currentsfrom reduction to enhancement, while manip-ulations that increase PKA activation levelsswitch the effect of 5-HT4 from enhancementto reduction. The molecular mechanism



underlying the changes in the polarity of 5-HT4 effects remains to be determined. Differ-ential PKA phosphorylation of different βsubunits of GABAA receptors provides onepotential mechanism. At low basal activationlevels, PKA may preferentially phosphorylateβ3 subunits first in response to a 5-HT4 ago-nist. This leads to the current enhancement.On the contrary, at high basal activation lev-els, PKA may cause the phosphorylation ofboth β1 and β3 subunits in response to theactivation of 5-HT4 receptors. The dominanteffect of β1 phosphorylation over β3 phospho-rylation leads to the current reduction.

How do different PFC pyramidal neuronshave varied basal PKA activation levels underphysiological conditions? The role of neuronalactivity was further tested (77). Several lines ofevidence indicate that the direction of 5-HT4

regulation is likely to be activity-dependent.First, only reduction of GABAA currents by a 5-HT4 agonist is observed in neurons isolatedfrom PFC slices with high neuronal activity.Secondly, the 5-HT4–mediated enhancement ofthe amplitude of GABAergic sIPSCs in PFCpyramidal neurons in slices is converted to areduction after KCI-induced elevation ofexcitability. Furthermore, it has been found

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Fig. 2. A neural computational module for the 5-HT4 actions in PFC pyramidal neurons. For those cells at the“high activity” state, the concomitant activation of PKA to a high level by 5-HT4 receptors and high neuronalactivity leads to a reduction of postsynaptic GABAA-receptor functions (“NAND” gate), and a reduction ofGABA-mediated inhibitory synaptic transmission, which results in the neurons being locked at the “high activ-ity” state. However, for those cells at the “low activity” state, the concomitant activation of PKA to a low level by5-HT4 receptors and low neuronal activity leads to an enhancement of postsynaptic GABAA-receptor functions(“OR” gate), and an enhancement of GABA-mediated inhibitory synaptic transmission, which results in the neu-rons being locked at the “low activity” state. “0”: logic 0 state; “1”: logic 1 state; “NAND” gate: a gate perform-ing the “NOT AND” function, i.e., the output is “0” only when two inputs are both “1”;”OR” gate: a gateperforming the logic that the output is “1” as long as there is at least one input at “1”;”NOT” gate: a gate per-forming the logic that the output is “1” when the input is “0” and vice versa. (Reproduced with permission fromref. 77.)

AU: Permission

filed?

that the PKA activation level is increased whenneuronal activity is enhanced by membranedepolarization in the PFC network. Thus, thedirection of 5-HT4 modulation of GABAA-receptor channels is dependent on the intracel-lular PKA activation level, which isdetermined by neuronal activity. Increasedneuronal activity can switch the effect of 5-HT4

receptors on GABAA channels from enhance-ment to reduction.

Based on the experimental data, a modelwhich illustrates the potential roles that 5-HT4

receptors may play in neural computation inPFC pyramidal neurons has been proposed(77). The activity-dependent bi-directional reg-ulation of GABAergic signaling by 5-HT4

receptors could potentially form a neural com-putational module namely, “Activity-LockedLoop (ALL)” (see Fig. 2), which could be sim-plified to resemble digital circuits controlled bylogic gates. This ALL module would allowserotonin, by acting on 5-HT4 receptors, to usekey molecules (e.g. PKA) within a single neu-ron to perform complex neural computation inmaintaining the activity state of a neuron.Non-physiological, activity-uncoupled pertur-bations of this module at different levels coulddisrupt the normal reinforcement of this ALLmodule, leading to altered output that couldhave dramatic behavioral consequences. Thisactivity-dependent bi-directional modulationof GABAA receptors by 5-HT4 receptors pro-vides a novel mechanism for neuromodulatorsto have either excitatory or inhibitory func-tions under different physiological conditions(33,83). This mechanism ensures that the mod-ulation is flexible, accurate, and dynamic.

Regulation of GABAergicTransmission by 5-HT1 Receptors

The 5-HT1A receptor is highly concentratedin the limbic system, especially in prefrontalcortex and hippocampus (84,48), as well as inthe raphe. Postsynaptic 5-HT1A receptors arefound only in the dendritic compartment and

associated with dendritic spines (85). Growingattention is being directed towards developingpharmacological agents that target 5-HT1A

receptors for the treatment of schizophrenia,anxiety, depression, and cognition disorders(86–88). Increased prefrontal 5-HT1A-receptordensity has been found in schizophreniapatients (28). 5-HT1A-receptor deficient miceshow consistently elevated anxiety alongsideantidepressant-like response (36). Activation of5-HT1A receptors has detrimental effects onworking memory, and 5-HT1A antagonistsameliorate the cognitive impairment (89).

A potential mechanism underlying theseactions of 5-HT1A receptors is the change ofsynaptic transmission and neuronal activitythrough regulation of ion channels. Previouselectrophysiological studies have shown that5-HT1A receptors can induce a membranehyperpolarization by activating the inwardlyrectifying potassium channels (90,91). 5-HT1A

receptors are also capable of inhibiting multi-ple classes of calcium channels (92,93). Appli-cation of 5-HT1A-receptor agonists has noeffect on postsynaptic GABAA-receptor cur-rents in pyramidal neurons of PFC and hip-pocampus (48,94). However, hippocampalslice recordings show that activation of 5-HT1A

receptors reduces polysynaptic fast- and slow-inhibitory postsynaptic potentials in CAI pro-jection neurons (94). Presynaptic mechanismsinvolving the inhibition of GABAergicinterneurons have been proposed for the 5-HT1A–mediated reduction of polysynapticinhibition (94). Whether 5-HT1A receptors elicita similar effect on GABAergic inhibitorysynaptic transmission in PFC slices remains tobe examined.

Another member of the 5-HT1 subfamily, 5-HT1B, is expressed in about 60% of PFC pyra-midal neurons (48), and localizedpredominantly on axon terminals (95). Intra-cellular recordings show that activation of 5-HT1B receptors in cingulate cortex depressesGABAergic inhibitory postsynaptic potentialsevoked by stimulation to the subcortical whitematter via a presynaptic mechanism (66).These data suggest that activation of presynap-



tic 5-HT1B-receptors reduces the release ofGABA at synapses onto PFC pyramidal neu-rons, and at synapses onto local feed-forwardinhibitory interneurons. Similarly, the GABAA-receptor-mediated synaptic input originatingfrom the striatum to substantia nigra parsreticulata neurons is also attenuated by presy-naptic 5-HT1B receptors (96). The mechanismsunderlying 5-HT1B-mediated inhibition ofGABAergic transmission are unclear.

Regulation of GABAergicTransmission by 5-HT3 Receptors

Unlike other G protein-coupled serotoninreceptors, 5-HT3 receptors are ion channels onplasma membrane (97,98). An inward currentcan be induced by 5-HT3-receptor activation ina variety of neurons (99,100). The current ismediated by a cationic influx, activated rapidlyupon application of serotonin and desensitizedupon prolonged exposure to serotonin.Immunohistochemical studies indicated that 5-HT3 receptors are expressed only in a subset ofGABAergic neurons in neocortex and hip-pocampus (101). Activation of 5-HT3 receptorsin these inhibitory interneurons evokes a largeand rapidly desensitizing inward current andinduces a transient enhancement of sIPSCs inthese brain regions (64,102). Though the func-tional significance of this selective expressionof 5-HT3 receptors is unclear, it is certain that ashort pulse of 5-HT can directly excite fast-spiking GABAergic interneurons, leading to atransient increase in GABAergic synapticactivity onto targets innervated by theseinterneurons. The enhanced inhibition mayunderlie the 5-HT3-mediated suppression ofthe firing rate of PFC neurons (103).

Conclusion

The serotonergic system is involved in theregulation of diverse psychophysiologicalprocesses including mood, aggression, percep-

tion, memory, and anxiety. To mediate thislarge array of brain functions, a complex set ofserotonin receptors has evolved. Alterations of5-HT-receptor activity have been shown tooccur in many psychiatric diseases. A numberof effective psychopharmacological agents forthese disorders have been developed whicheither specifically alter brain levels of serotoninor bind to 5-HT-receptor subtypes. To searchfor new therapeutic agents with higher speci-ficity and efficacy, but lower side effects andtoxicity, we need to know more about thephysiological functions of serotonin in criticalbrain regions such as the prefrontal cortex.Genetic and behavior studies have providedimportant knowledge about the actions ofserotonin at the systematic level (34–36). Thecellular and molecular mechanisms underly-ing serotonin functions are lacking. By combin-ing electrophysiological, pharmacological,biochemical, and molecular analyses, the datareviewed here demonstrates that by activatingdifferent receptors, serotonin plays an impor-tant role in regulating GABAergic inhibition inPFC. The information gained from these stud-ies should provide an important basis forunderstanding physiological functions of sero-tonergic system in the complex cortical neuro-circuits under normal and patahologicalconditions.

From the postsynaptic loci, 5-HT2 receptorson PFC pyramidal neurons inhibit GABAA-channel activity (48), while 5-HT4 receptorsexert an activity-dependent bi-directional reg-ulation of GABAA channel activity (77). Withthe convergence of both 5-HT2/PKC and 5-HT4/PKA pathways on the same target—post-synaptic GABAA receptors, serotonin can exerta complex regulation of the GABAergicinhibitory transmission in PFC. For those pyra-midal neurons that express 5-HT2, but not 5-HT4 receptors, 5-HT may induce a reduction ofpostsynaptic GABAA-receptor function justthrough the 5-HT/PKC-mediated cascade. Forthose pyramidal neurons that express both 5-HT2 and 5-HT4 receptors, the 5-HT effect onpostsynaptic GABAA receptors could be com-plicated. The 5-HT2/PKC-induced change of

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GABAA receptor γ2 or β2 subunit phosphoryla-tion would compete with the 5-HT4/PKA-induced change of GABAA receptor β1 or β3subunit phosphorylation, and therefore deter-mine the final effect of 5-HT on the channelfunction. To determine which of the two modi-fications plays the dominant role may dependon a variety of factors, such as the relativeabundance and subcellular localization of 5-HT2 vs 5-HT4 receptors, basal levels of phos-phorylated GABAA receptors by constitutivelyactive PKC vs PKA, efficacy in alteringGABAA-receptor phosphorylation by the 5-HTreceptor-activated PKC/RACk1 vs PKA/AKAP complex, and varied activity states ofdifferent PFC pyramidal neurons.

In addition to the postsynaptic modulation ofGABAA receptors by 5-HT in pyramidal neu-rons, the effect of 5-HT on the excitability ofGABAergic interneurons and on the releaseprobability at GABAergic terminals also plays akey role in determining the impact of 5-HT oninhibitory transmission. On one hand, 5-HTcould enhance GABAergic transmission bydirectly exciting GABAergic interneurons viathe activation of 5-HT2A or 5-HT3 receptors (64).However, 5-HT could also suppress GABAergictransmission via the activation of presynaptic 5-HT1A or 5-HT1B receptors (94,66). To establishwhich of the two effects plays the dominant rolemay depend on the expression and properties(e.g., binding affinity and agonist-induceddesensitization) of these 5-HT receptors, as wellas their coupling to intrinsic ion channels(64–68) or release machinery. It has been shownthat serotonin at the crayfish neuromuscularjunction increases the number of vesicles avail-able for transmitter release, by either an increasein the number of vesicles at each release site, oran activation of previously nonsecreting orsilent synapses (104). Further studies need to beexplored in order to examine whether serotoninin central neurons also regulate synaptic vesiclerecycling, and what receptors are mediating thispresynaptic effect of serotonin on synaptictransmission.

With so many different receptors acting atboth pre- and postsynaptic sites, it is hard to

predict what will happen to PFC neuronal activ-ity in response to serotonin. In vivo studies havedemonstrated that the predominant effect of 5-HT on cortical pyramidal neurons is an inhibi-tion of spontaneous spiking (105,106). Thepresynaptic increase of GABA transmissionmediated by 5-HT2 and 5-HT3 receptors (64),together with the enhancement of postsynapticresponses to GABA by 5-HT4 receptors in neu-rons with “low activity” (77), could be one ofthe underlying mechanisms for the inhibitoryactions of 5-HT. However, in vitro, studies sug-gest that 5-HT induces depolarization andaction potential firing in pyramidal neurons(66,67). The decrease of postsynaptic responsesto GABA by 5-HT2 receptors (48) and by 5-HT4

receptors in neurons with “high activity” (77),as well as the presynaptic suppression of GABAtransmission mediated by 5-HT1A and 5-HT1B

receptors, could be one of the originating mech-anisms for the excitatory actions of 5-HT.Indeed, serotonergic regulation of glutamater-gic transmission (107,108) could be anotherimportant mechanism to regulate PFC neuronalactivity. The complex cellular expression andsubcellular locations of different 5-HT receptors,their coupling to different intracellular signal-ing components, and their impact on multipletargets make it too simplistic to catagorize theactions of 5-HT receptors as excitatory vsinhibitory, or cooperative vs antagonistic. How-ever, integration of all the information shouldhelp us to understand how serotonin, by actingon various receptor subtypes, modulates theelectrophysiological properties of PFC neuronsin a coordinated fashion to achieve their precisefunctions within neuronal networks. Elucida-tion of signaling components critically engagedin serotonergic actions could provide the poten-tial targets for novel pharmacological agents inthe treatment of neuropsychiatric disorders.

Acknowledgment

The author would like to thank Dr. Jian Fengfor critical reading and discussion of the manu-script. The work in the author’s laboratory is



supported by the National Science Foundation(IBN-0117026), the National Institute of Health(MH63128) and the National Alliance forResearch on Schizophrenia and Depression(Young Investigator Award).

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Regulation of GABAergic Inhibition by Serotonin …zhenyan/5HT+GABA-review.pdfthe frontal lobes. The anatomical organization of primate PFC can be divided into three major subregions: